Department of Molecular and Medical Pharmacology, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan.
Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, 162-8655, Japan.
Biochem Biophys Res Commun. 2022 Dec 25;636(Pt 1):89-95. doi: 10.1016/j.bbrc.2022.10.072. Epub 2022 Oct 21.
Nicotinamide adenine dinucleotide (NAD), a biological molecule integral to redox reactions involved in multiple cellular processes, has the potential to treat nonalcoholic fatty liver diseases (NAFLDs) and nonalcoholic steatohepatitis (NASH). Nicotinamide mononucleotide adenylyltransferase (Nmnat1), one of the NAD biosynthesizing enzymes, plays a central role in all NAD metabolic pathways and it is vital to embryonic development. However, the function of Nmnat1 in metabolic pathology and, specifically, in the development and progression of NAFLD and NASH remains unexplored. First, we generated hepatic Nmnat1 knockout (H-Nmnat1) mice to investigate the physiological function of Nmnat1 and found that NAD levels were significantly lower in H-Nmnat1 mice than control mice. However, H-Nmnat1 mice appeared normal with comparable metabolic activity. Next, we used three different diet-induced NASH models to assess the pathophysiological role of Nmant1 in metabolic disorders and discovered that hepatic loos of Nmnat1 decreased 35%-40% of total NAD in an obese state. Nevertheless, our analysis of phenotypic variations found comparable body composition, gene expression, and liver histology in all NASH models in H-Nmnat1 mice. We also found that aged H-Nmnat1 mice exhibited comparable liver phenotypes with control mice. These findings suggest that Nmnat1 has a redundancy to the pathophysiology of obesity-induced hepatic disorders.
烟酰胺腺嘌呤二核苷酸（NAD）是一种生物分子，是参与多种细胞过程中氧化还原反应的重要组成部分，具有治疗非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）的潜力。烟酰胺单核苷酸腺苷酰转移酶（Nmnat1）是 NAD 生物合成酶之一，在所有 NAD 代谢途径中发挥核心作用，对胚胎发育至关重要。然而，Nmnat1 在代谢病理学中的功能，特别是在 NAFLD 和 NASH 的发展和进展中的功能尚未得到探索。首先，我们生成了肝脏 Nmnat1 敲除（H-Nmnat1）小鼠，以研究 Nmnat1 的生理功能，发现 H-Nmnat1 小鼠的 NAD 水平明显低于对照小鼠。然而，H-Nmnat1 小鼠的代谢活性相当，外观正常。接下来，我们使用三种不同的饮食诱导的 NASH 模型来评估 Nmant1 在代谢紊乱中的病理生理作用，发现肥胖状态下肝脏 Nmnat1 的缺失导致总 NAD 减少了 35%-40%。然而，我们对表型变化的分析发现，在所有 NASH 模型中，H-Nmnat1 小鼠的身体组成、基因表达和肝组织学都具有可比性。我们还发现，年老的 H-Nmnat1 小鼠的肝脏表型与对照小鼠相当。这些发现表明，Nmnat1 对肥胖引起的肝紊乱的病理生理学具有冗余性。
